PROJECT SUMMARY Gene regulatory networks (GRNs) are central to almost all biological processes. Research in my laboratory focusses on understanding the structure and logic of human GRNs with the ultimate goal of devising strategies for therapeutic interventions. Current gaps in our understanding of GRNs include: determining how combinations of transcription factors (TFs) regulate specific target gene expression patterns, identifying mechanisms by which different genes are co-regulated to effect a given biological response, determining how GRNs are rewired in response to environmental cues, and designing strategies to manipulate GRNs to modulate biological outcomes. Cytokines present an ideal model system to study GRNs because cytokines genes are highly regulated at the transcriptional level and because this regulation involves a complex interplay between cell type-specific TFs and TFs activated by different signaling pathways. In this proposal, we will investigate the structure and regulatory logic of the cytokine GRN by integrating complementary methods to map protein-DNA interactions, functional perturbations, and phenotypic characterizations. Further, we will determine the mechanisms by which virally-encoded TFs perturb the cytokine GRN by determining the targeted cytokine regulatory regions and targeted host proteins such as TFs, cofactors, and signaling proteins. Overall, the proposed studies will identify general principles and generate a framework to study and manipulate GRNs which will ultimately lead to novel strategies impacting human health.